Chvatal Stacie A, Kim Young-Tae, Bratt-Leal Andres M, Lee Hyunjung, Bellamkonda Ravi V
Neurological Biomaterials and Therapeutics, Laboratory for Neuroengineering, Wallace H Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30332, USA.
Biomaterials. 2008 Apr;29(12):1967-75. doi: 10.1016/j.biomaterials.2008.01.002. Epub 2008 Feb 5.
Methylprednisolone (MP) has been shown to reduce acute inflammation resulting from a secondary damage cascade initiated by the primary physical injury to the spinal cord. The current clinical practice for delivering systemic MP is inefficient, and high doses are required, resulting in adverse, undesired, dose-related side effects in patients. Here, we report a novel, minimally invasive, localized drug delivery system for delivering MP to the contused adult rat spinal cord that potentially side-steps the deleterious consequences of systemic cortico-steroid therapy. MP was encapsulated in biodegradable PLGA based nanoparticles (NP), and these nanoparticles were embedded in an agarose hydrogel for localization to the site of contusion injury. To visualize and quantify its spatial distribution within the injured spinal cord, MP was conjugated to Texas-red cadaverine prior to encapsulation in nanoparticles. When delivered via the hydrogel-nanoparticle system, MP entered the injured spinal cord and diffused up to 1.5mm deep and up to 3mm laterally into the injured spinal cord within 2 days. Furthermore, topically delivered MP significantly decreased early inflammation inside the contusion injured spinal cord as evidenced by a significant reduction in the number of ED-1(+) macrophages/activated microglia. This decreased early inflammation was accompanied by a significantly diminished expression of pro-inflammatory proteins including Calpain and iNOS. Additionally, topically delivered MP significantly reduced lesion volume 7 days after contusion injury. The minimally invasive MP delivery system reported in this study has the potential to enhance the effectiveness of MP therapy after contusion injury to the spinal cord and avoid the side effects arising from high dose cortico-steroid therapy.
甲基泼尼松龙（MP）已被证明可减轻因脊髓原发性物理损伤引发的继发性损伤级联反应所导致的急性炎症。目前全身性给予MP的临床实践效率低下，且需要高剂量，这会给患者带来不良的、不期望的、与剂量相关的副作用。在此，我们报告一种新型的、微创的局部药物递送系统，用于将MP递送至成年大鼠脊髓挫伤部位，这可能避免全身皮质类固醇治疗的有害后果。MP被包裹在基于可生物降解聚乳酸-羟基乙酸共聚物（PLGA）的纳米颗粒（NP）中，并且这些纳米颗粒被嵌入琼脂糖水凝胶中，以定位到挫伤损伤部位。为了可视化并量化其在损伤脊髓内的空间分布，在将MP包裹于纳米颗粒之前，将其与德克萨斯红尸胺偶联。当通过水凝胶-纳米颗粒系统递送时，MP进入损伤脊髓，并在2天内扩散至损伤脊髓内达1.5毫米深、3毫米宽。此外，局部递送的MP显著降低了挫伤损伤脊髓内的早期炎症，这可通过ED-1（+）巨噬细胞/活化小胶质细胞数量的显著减少得到证明。这种早期炎症的减轻伴随着包括钙蛋白酶和诱导型一氧化氮合酶在内的促炎蛋白表达的显著降低。另外，局部递送的MP在挫伤损伤7天后显著减小了损伤体积。本研究中报道的微创MP递送系统有可能提高脊髓挫伤损伤后MP治疗的有效性，并避免高剂量皮质类固醇治疗引起的副作用。
